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• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6813—Hybridisation assays
  • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6813—Hybridisation assays
  • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
  • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
  • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

• This invention is related to methods, systems and computer program products for determining the biological effect and/or activity of drags, chemical substances and/or pharmaceutical compositions using their effect on DNA-methylation as a marker for their biological effect(s).
• the invention is further related to the use of the inventive methods, systems and computer program products in obtaining new biologically active compounds which can be used as so- called Collectorlead"-compounds for new and effective medicaments and treatment strategies of, in particular, human, diseases.
• combinatorial chemistry involves screening of a specific (or a set of specific) compound with a vast number of potential biological candidate substances (for example, proteins) that might interact with the compound. Interacting partners are selected and used for further screening. Initially screened and isolated compounds can be used as heavilylead"- compounds for the development of biologically active compounds useful for treatment of diseases.
• WO 00/71742 describes theticianmaniage" of solid-state electronics and neuronal function to create a new high-throughput electrophysiological assay to determine a compound's acute and chronic effect on cellular function.
• Electronics, surface chemistry, biotechnology, and fundamental neuroscience are integrated to provide an assay where the reporter element is an anay of electrically active cells.
• This innovative technology was applied to neurotoxicity, and to screening compounds from combinatorial chemistry, gene function analysis, and basic neuroscience applications. Further disclosed are algorithms to analyze the action potential peak shape differences to indicate the pathway(s) affected by the presence of a new drug or compound; from that, aspects of its function in that cell are deduced. This observation is said to be exploited to determine the functional category of biochemical action of an unknown compound.
• WO 00/23458 describes templated combinatorial chemical libraries comprised of a plurality of bifunctional molecules having both a chemical compound and a nucleic acid tag that defines the structure of the chemical compound and directs its synthesis.
• the screening of a combinatorial chemistry library involves a screening for a multitude of different possible reactions and/or interactions of the compounds to be analysed with the interacting partners. Therefore, the reaction conditions are assumed crucial for the result of the screening.
• a compound which shows an interaction with a target in such a combinatorial assay in vitro might exhibit completely different reaction conditions in vivo which makes prediction of an effective compound very difficult and unreliable.
• an interaction in an in vitro combinatorial chemistry screening assay can always only give a hint for a potential biological function of the screened compound in vivo.
• combinatorial chemistry screening involves a necessary second step; once a potential target/lead compound has been identified/found, the biological effect still has to be confirmed/determined in an in vivo context. This makes compound identification using this method unpredictable, slow and costly.
• the first method is based in principle on the use of restriction endonucleases (RE), which are methylation-sensitive".
• REs are characterized in that they produce a cut in the DNA at a certain DNA sequence which is usually 4-8 bases long. The position of such cuts can be detected by gel electrophoresis, transfer to a membrane and hybridization. Methylation-sensitive means that certain bases within the recognition sequence must be unmethylated for the step to occur. The band pattern after a restriction cut and gel electrophoresis thus changes depending on the methylation pattern of the DNA. However, most CpG that can be methylated are outside of the recognition sequences of REs, and thus cannot be examined. The sensitivity of this method is extremely low (Bird, A. P., Southern, E.
• a variant combines PCR with this method; an amplification by two primers located on both sides of the recognition sequence occurs after a cut only if the recognition sequence is in the methylated form.
• the sensitivity theoretically increases to a single molecule of the target sequence; however, only individual positions can be examined, at great cost (Shemer, R. et al., PNAS 93, 6371-6376).
• the second variant is based on the partial chemical cleavage of whole DNA, using the model of a Maxam-Gilbert sequencing reaction, ligation of adaptors to the ends thus generated, amplification with generic primers, and separation by gel electrophoresis.
• This method defined regions having a size of less than thousands of base pairs can be examined.
• the method is so complicated and unreliable that it is practically no longer used (Ward, C, et al., J. Biol. Chem. 265, 3030-3033).
• a new method for the examination of DNA to determine the presence of 5-methylcytosine is based on the specific reaction of bisulfite with cytosine. The latter is converted under appropriate conditions into uracil, which, as far as base pairing is concerned, is equivalent to thy- midine, and which also corresponds to another base. 5-Methylcytosine is not modified. As a result, the original DNA is converted in such a manner that methylcytosine, which originally could not be distinguished from cytosine by its hybridisation behaviour, now can be detected by "normal" molecular biological techniques. All of these techniques are based on base pairing, which can now be completely exploited.
• the state of the art is defined by a method which includes the DNA to be examined in an agarose matrix, intended to prevent the diffusion and renaturing of the DNA (bisulfite reacts only with single- stranded DNA) and to replace all precipitation and purification steps by rapid dialysis (Olek, A., et al., Nucl. Acids. Res. 24, 5064-5066).
• a method which includes the DNA to be examined in an agarose matrix, intended to prevent the diffusion and renaturing of the DNA (bisulfite reacts only with single- stranded DNA) and to replace all precipitation and purification steps by rapid dialysis (Olek, A., et al., Nucl. Acids. Res. 24, 5064-5066).
• individual cells can be examined, which illustrates the potential of the method.
• this method is not capable of reliably analyzing minute fragments from small sample quantities. In spite of protection against diffusion, such samples are lost through the matrix.
• VHL von Hippel-Lindau
• genes are depicted in the listing of genes that is enclosed in this application and are associated with, for example, diseases related to angiogenesis, apoptosis, behavior, disorders of the cell cycle, cell signalling, developmental disorders, diseases related with DNA adducts, DNA damage, disorders in DNA replication, gene regulation, diseases related to immunological disorders, disturbances of the metabolism, metastasis, diseases related to miscellaneous clinical syndromes, pharmacological conditions, diseases related to a disturbed signal transduction, disturbed transcription, and tumour suppression oncogene related diseases.
• an object of the invention is to provide methods, systems and computer program products for determining the biological effect and/or activity of drugs, chemical substances and/or pharmaceutical compositions using their effect on DNA-methylation as a marker for their biological effect(s).
• a further object of the invention is to provide the inventive systems, methods and computer program products for their use in determining a drug, chemical substance and/or pharmaceutical composition that is biologically effective and/or active.
• a further object of the invention is to provide biologically effective and/or active drags, chemical substances and/or pharmaceutical compositions, which can be obtained using a method according to the invention.
• a further object of the invention is to provide the biologically effective and/or active dmg, chemical substance and/or pharmaceutical composition which is obtained using a method according to the invention for the use in a treatment of a disease and/or medical condition.
• a further object of the invention is to provide systems, methods and computer program products for performing any of the inventive methods.
• a further object of the invention is to provide a treatment of a disease and/or medical condition, based on a biologically effective and/or active drug, chemical substance and/or pharmaceutical composition according to the invention.
• This object is solved according to the present invention by providing a method for determining the biological effect and or activity of at least one drug, chemical substance and/or pharmaceutical composition, which comprises the steps of:
• the present invention uses the modifications in the methylation pattern of the DNA for screening of biologically effective substances.
• the invention uses the fact that the biological effect of a potentially biologically effective drug, chemical substance or pharmaceutical composition results in a modification of the DNA-methylation pattern of a cell or biological test system upon contact with the drug, chemical substance or pharmaceutical composition. Analysis of the modification of the pattern allows a direct conclusion about the biological effect of the drug, chemical substance or pharmaceutical composition in vivo and its potential application in the treatment of diseases or medical conditions.
• the invention has several advantages in comparison to other screening methods, in particular combinatorial chemistry.
• the reaction conditions of the drug, chemical substance or pharmaceutical composition with the biological test system can be controlled in a very reliable manner. Modifications can be applied in a highly reproducible way due to the simplicity of the assay procedure and conditions.
• the analysis of the methylation pattern of the DNA allows screening of the in vivo effect of the substance in a one-step procedure using one controllable reaction (namely, the bisulfite treatment in order to look at the methylation status) instead of millions of unknown interactions between drugs, chemical substances or pharmaceutical compositions compounds and compounds of the cell or biological test system.
• the inventive method allows the inclusion of personal data into the selection/analysis procedure which allows for a personalised screening of drugs, chemical substances or pharmaceutical compositions.
• the biological sample is obtained by means of a biopsy, by means of an operation on an individual, by means of a dissection, derived from a preserved biological sample, collected from body fluid(s) and/or collected directly from the environment.
• a biopsy by means of an operation on an individual
• a dissection derived from a preserved biological sample, collected from body fluid(s) and/or collected directly from the environment.
• the only prerequisite for such a biological sample is to contain DNA which can be used directly or indirectly for the methylation analysis.
• the biological sample comprises a eucaryotic and/or procaryotic cell line, a biopsy sample, blood, sputum, faeces, urine, cerebral liquid, tissue embedded in paraffin, tissue derived from eyes, intestine, brain, heart, prostata, kidney, lung, breast or liver, histological samples or a combination thereof.
• a prefened method according to the invention is characterised in that the biological sample is obtained from biological material of healthy and/or diseased individuals.
• diseases include all diseases and/or medical conditions which involve a modification of the DNA methylation of the cell and include, for example, unwanted side effects of medicaments, cancers, metastasis, dysfunctions, damages or diseases of the central nervous system (CNS), aggressive symptoms or behavioural disorders, clinical, psychological and social consequences of brain injuries, psychotic disorders and disorders of the personality, dementia and/or associates syndromes, cardiovascular diseases, malfunctions or damages, diseases, malfunctions or damages of the gastrointestine, diseases, malfunctions or damages of the respiratory system, injury, inflammation, infection, immunity and/or reconvalescence, diseases, malfunctions or damages as consequences of modifications in the developmental process, diseases, malfunctions or damages of the skin, muscles, connective tissue or bones, endocrine or metabolic diseases, malfunctions or damages, headache, and sexual malfunctions or combinations thereof, leukemia, head and neck cancer, Hodgkin's disease, gastric cancer, prostate cancer, renal cancer
• the biological samples A and B are obtained from the identical individual, tissue, cell or other biological material.
• the biological samples A and B are taken before, during and/or after onset of a treatment with said drug, chemical substance or pharmaceutical composition.
• An even more prefened method according to the invention further comprises the step of isolating DNA from the said samples before analysing the level of cytosine methylation at chosen sites in said isolated DNA.
• the isolation of the DNA for performing the inventive method can be characterised in that the isolation of said DNA contained in said biological sample comprises isolating subcellular compartments, organelles, macromo- lecular stractures and multiprotein complexes, partial or complete preparation of the DNA and/or partial digestion of the material with an enzyme selected from proteases, RNAses and/or DNAses or combinations thereof.
• the pre-isolation of only parts of the cells, like organelles or the like allows a pre-selection of the genes to be analysed. Other methods mentioned above can limit the amount of cellular debris which could interfere with the further analysis.
• the analysis of the level of cytosine methylation comprises chemical treatment with bisulphite, hydrogen sulphite or di- sulphite, polymerase chain reaction (PCR), hybridisation analyses, sequencing, mass spec- trometry and fluorescent, enzymatic, radioactive, dye and/or antibody labelling.
• PCR polymerase chain reaction
• all methods for the analysis of the methylation statuses at selected sites of the DNA can be employed. Such methods are known to the skilled artisan and are described in, for example, Dahl et al., StammAnalysis of in vivo methylation.” Methods Mol Biol 2000;130:47-57; Zhou Y.
• Another preferred method according to the invention is characterised in that all potentially methylated sites of the DNA are analysed. Such sites usually include all so-called JeffCpG"- islands on a given DNA sequence and are readily detectable by the person skilled in the art.
• the level of at least two cytosine methylation sites is analysed in parallel, in order to test the potential effect of the drug, chemical substance or pharmaceutical composition on more than one methylation site.
• the level of at least 100 cytosine methylation sites is analysed in parallel. The analysis of a multitude of sites in parallel allows for both an effective screening and a statistically highly relevant result of the method.
• the effect of the drug, chemical substance or pharmaceutical composition to be analysed on the biological cell, tissue or other biological system results in a modification of the expression of the genes of the respective cell, tissue or other biological system. Nevertheless, it is further prefened to analyse methylation sites that are located in methylation relevant regions of the DNA other than the genes themselves and which comprise complete genes and/or promoters, introns, first exons and or enhancers. From the analysis of the methylation sites which are relevant for the expression of a certain gene, but not localised inside the sequence of the gene itself, the effect of the site for the expression of the gene can be readily extrapolated by the person skilled in the art.
• methylation sites are located in methylation relevant regions of genes related with unwanted side effects of medicaments, cancers, metastasis, dysfunctions, damages or diseases of the central nerval system (CNS), aggressive symptoms or behavioural disorders, clinical, psychological and social consequences of brain injuries, psychotic disorders and disorders of the personality, dementia and/or associates syndromes, cardiovascular diseases, malfunctions or damages, diseases, malfunctions or damages of the gastrointestine, diseases, malfunctions or damages of the respiratory system, injury, inflammation, infection, immunity and/or reconvalescence, diseases, malfunctions or damages as consequences of modifications in the developmental process, diseases, malfunctions or damages of the skin, muscles, connective tissue or bones, endocrine or metabolic diseases, malfunctions or damages, headache, and sexual malfunctions or combinations thereof.
• CNS central nerval system
• genes that are related to diseases related to angiogenesis, apoptosis, behavior, disorders of the cell cycle, cell signalling, developmental disorders, diseases related with DNA adducts, DNA damage, disorders in DNA replication, gene regulation, diseases related to immunological disorders, disturbances of the metabolism, metastasis, diseases related to miscellaneous clinical syndromes, medical and pharmacological conditions, diseases related to a disturbed signal transduction, disturbed transcription, and tumour suppression/oncogene related diseases are depicted in the listing enclose in this application.
• a method according to the invention which is characterised in that the methylation sites are located in methylation relevant regions of genes related with leukemia, head and neck cancer, Hodgkin's disease, gastric cancer, prostate cancer, renal cancer, bladder cancer, breast cancer, Burkitt's lymphoma, Wilms tumor, Prader-Willi/Angelman syndrome, ICF syndrome, dermatofibroma, hypertension, pediatric neurobiological diseases, autism, ulcerative colitis, fragile X syndrome, and Huntington's disease.
• the analysed methylation sites are disease specific and/or personalised. This means, that a selection of sites is performed before the methylation analysis which allows a search whichraclooks" for an effect of a drag, chemical substance or pharmaceutical composition that is specifically suited (designed) for the individual need of the patient.
• a further prefened method according to the invention is characterised in that the selection is based on the result of at least two individual rows of analyses. This will reduce the statistical enor for the value of the methylation sensitivity of a selected site with an only limited increase of the costs for the analysis.
• the selection is performed in such a way to give a knowledge base comprising only one set of selected sites.
• the knowledge base will comprise only respondentson" and Wegoff type of data which allows for a very simple decision between different effects of different drugs, chemical substances or pharmaceutical compositions.
• the selection is performed in such a way to result in a knowledge base comprising different classes of selected sites.
• Such classes can be refened to as hearing quality classes" which allows for a much more differentiated analysis of the effect of the drugs, chemical substances or pharmaceutical compositions to be analysed.
• the term as used herein comprises all different possibilities of grouping the different sites. Such groupings could, for example, include different importance for the selected sites for the analysis of the biological effect as well as statistical preciseness and/or quality of the analysis data of the selected site.
• the selection is at least partially performed automatically by means of a suited automate, e.g. a computer device.
• a suited automate e.g. a computer device.
• Such device would be equipped with the necessary software for the analysis of the methylation sites and could be connected to an inter- or intranet, be part of a neural network or the like.
• the necessary data/information for the analyses can be present on the system directly or at a remote source, to which the device is directly or indirectly connected, for example via the internet.
• at least two sites are selected in parallel. More preferably, at least 100 sites are selected in parallel.
• all or only a part of the sites of the knowledge base can be used.
• additional information about the biological sample is used for the conclusion. This additional information can comprise personal patient data, disease specific data, prior treatment data and/or additional methylation specific data.
• the conclusion is based on the result of at least two individual rows of analyses.
• This provides for an internal control run of the data which is used for the conclusion and increases the preciseness of the results.
• the conclusion is performed by a computer system.
• Such device would be equipped with the necessary software for the conclusion and could be connected to an inter- or intranet, be part of a neural network or the like.
• the necessary data/information for the conclusion can be present on the system directly or at a remote source, to which the device is directly or indirectly connected, for example via the internet.
• steps a) to d) are repeated.
• Repeating the method of the invention suits several different purposes.
• Third, the inventive method can be repeated after a certain time after taking the first sample in order to provide for a monitoring of the effect of the drug(s), chemical substance(s) or pharmaceutical composition(s) to be analysed over time. This information could be included in the results of the analysis in order to provide a more precise picture of the biological effect of the drag, chemical substance or pharmaceutical composition to be analysed. With the commonly used method of combinatorial chemistry, this aspect can not be analysed since this method uses a provoked" system for the analysis of the compounds.
• the method of the invention is characterised in that the identical biological sample, different biological samples or a combination thereof is used in steps a) and/or b). In another embodiment the method of the invention is characterised in that steps c) to d) are repeated.
• the number of repeating suitscycles" of the invention can vary depending on the indi- vidual case, e.g. depending on the quality of the sample to be analyse. One possibility would be to repeat the method of the invention for at least 5 to 50 times.
• such method according to the invention is characterised in that the method is at least partially performed by means of a suited automate, for example a robot and/or a computer system.
• a suited automate for example a robot and/or a computer system.
• the inventive method can be conveniently automated and/or computerized and respective devices and programs are readily known to the person skilled in the art.
• a still further object of the invention is the use of the inventive method for determining at least one drug, chemical substance and/or pharmaceutical composition that is biologically effective and/or active.
• CNS central nerval system
• said at least one drag, chemical substance and/or pharmaceutical composition is biologically effective and/or active in the treatment of leukemia, head and neck cancer, Hodgkin's disease, gastric cancer, prostate cancer, renal cancer, bladder cancer, breast cancer, Burkitt's lymphoma, Wilms tumor, Prader-Willi/Angelman syndrome, ICF syndrome, dermatofibroma, hypertension, pediatric neurobiological diseases, autism, ulcerative colitis, fragile X syndrome, and Huntington's disease.
• Another aspect of the invention is a biologically effective and or active drug, chemical substance and/or pharmaceutical composition which is obtained according to a method according to the invention. Accordingly, another aspect of the invention is, to use such a biologically effective and/or active drug, chemical substance and/or pharmaceutical composition according for the treatment of a disease and/or medical condition.
• such disease and/or medical condition is related to unwanted side effects of medicaments, cancers, metastasis, dysfunctions, damages or diseases of the central nerval system (CNS), aggressive symptoms or behavioural disorders, clinical, psychological and social consequences of brain injuries, psychotic disorders and disorders of the personality, dementia and/or associates syndromes, cardiovascular diseases, malfunctions or damages, diseases, malfunctions or damages of the gastrointestine, diseases, malfunctions or damages of the respiratory system, injury, inflammation, infection, immunity and/or reconvalescence, diseases, malfunctions or damages as consequences of modifications in the developmental process, diseases, malfunctions or damages of the skin, muscles, connective tissue or bones, endocrine or metabolic diseases, malfunctions or damages, headache, and sexual malfunctions or combinations thereof.
• CNS central nerval system
• diseases would be diseases related to angiogenesis, apoptosis, behavior, disorders of the cell cycle, cell signalling, developmental disorders, diseases related with DNA adducts, DNA damage, disorders in DNA replication, gene regulation, diseases related to immunological disorders, disturbances of the metabolism, metastasis, diseases related to miscellaneous clinical syndromes, medical and pharmacological conditions, diseases related to a disturbed signal transduction, disturbed transcription, and tumour suppression/oncogene related diseases.
• said disease and/or medical condition is leukemia, head and neck cancer, Hodgkin's disease, gastric cancer, prostate cancer, renal cancer, bladder cancer, breast cancer, Burkitt's lymphoma, Wilms tumor, Prader-Willi/Angelman syndrome, ICF syndrome, dermatofibroma, hypertension, pediatric neurobiological diseases, autism, ulcerative colitis, fragile X syndrome, and/or Huntington's disease.
• Another aspect of the invention is related to a method for the treatment of a disease and/or medical condition, which comprises: a) providing at least one biologically effective and/or active drug, chemical substance and/or pharmaceutical composition obtained according to the invention; and b) installing a treatment for the disease and/or medical condition comprising application of the at least one biologically effective and/ or active drug, chemical substance and/or pharmaceutical composition to the patient in need.
• a method for the treatment of a disease and/or medical condition which comprises: a) providing at least one biologically effective and/or active drug, chemical substance and/or pharmaceutical composition obtained according to the invention; and b) installing a treatment for the disease and/or medical condition comprising application of the at least one biologically effective and/ or active drug, chemical substance and/or pharmaceutical composition to the patient in need.
• Prefened in this context is a method according to the invention wherein said specific treatment is a disease specific and/or personalised. Such personalised treatment cannot reasonably be achieved with methods of treatment according to the state of the art as present.
• CNS central nerval system
• inventive methods for the treatment of unwanted side effects of medicaments, cancers, dysfunctions, damages or diseases of the central nerval system (CNS), aggressive symptoms or behavioural disorders, clinical, psychological and social consequences of brain injuries, psychotic disorders and disorders of the personality, dementia and/or associates syndromes, cardiovascular diseases, malfunctions or damages, diseases, malfunctions or damages of the gastrointestine, diseases, malfunctions or damages of the respiratory system, injury, inflammation, infection, immunity and/or reconvalescence, diseases, malfunctions or damages as consequences of modifications in the developmental process, diseases, malfunctions or damages of the skin, muscles, connective tissue or bones, endocrine or metabolic diseases, malfunctions or damages, headache, and sexual malfunctions or combinations thereof.
• CNS central nerval system
• inventive method can be used for the treatment of diseases and/or conditions which are related to the genes as depicted in the listing of genes enclosed in this application, namely genes related to angiogenesis, apoptosis, behavior, disorders of the cell cycle, cell signalling, developmental disorders, diseases related with DNA adducts, DNA damage, disorders in DNA replication, gene regulation, diseases related to immunological disorders, disturbances of the metabolism, metastasis, diseases related to miscellaneous clinical syndromes, medical and pharmacological conditions, diseases related to a disturbed signal transduction, disturbed transcription, and tumour suppression/oncogene related diseases.
• diseases and/or conditions which are related to the genes as depicted in the listing of genes enclosed in this application, namely genes related to angiogenesis, apoptosis, behavior, disorders of the cell cycle, cell signalling, developmental disorders, diseases related with DNA adducts, DNA damage, disorders in DNA replication, gene regulation, diseases related to immunological disorders, disturbances of the metabolism, metastasis, diseases related to miscellaneous clinical syndromes
• the method according to the invention for the treatment of leukemia, head and neck cancer, Hodgkin's disease, gastric cancer, prostate cancer, renal cancer, bladder cancer, breast cancer, Burkitt's lymphoma, Wilms tumor, Prader-Willi/Angelman syndrome, ICF syndrome, dermatofibroma, hypertension, pediatric neurobiological diseases, autism, ulcerative colitis, fragile X syndrome, and Huntington's disease.
• TNF Tumour Necrosis Factor
• the colon cancer cell line HAT-29P218 was treated with 10 ng/ml TNF-alpha 1 and 9 ng/ml TGF-beta 1 for 10 days.
• the media was exchanged after each treatment of 48 h and followed by supplementation TGF-alpha 1 and TGF-beta 1 at the indicated concentrations.
• the cells of the cytokine treated and the untreated control cell line cultures were collected by centrifugation and the chromosomal DNA was prepared using QIAamp DNA Mini Kit as recommended by the manufacturer (Quiagen, Hilden, Germany).
• the chromosomal DNAs were bisulphite treated as published, for example, according to Olek et al. (ref?**) 6 different multiplex PCR reactions were performed on the 3 bisulphite DNA samples (untreated control, TGF-alpha 1 and TGF-beta 1 treated samples) using Cy5 -labelled primer. The products of the methylation specific PCR reactions performed on the same DNA samples were combined. These complex mixtures of 64 PCR products derived from the three DNA samples were comparatively hybridised onto oligo micro anays representing 256 CpG and the methylation statuses of the CpGs were analysed (see, for example, WO 99/28498).
• a peptide library was prepared in a 96-well culture plate which contained overlapping peptide fragments derived from the peptide sequence of human serum albumine (HSA).
• HSA human serum albumine
• VIP vasoactive intestinal peptide
• PACAP pituitary adenylate cyclase-activating polypeptide
• Both peptides are known to protect T cells from activation-induced cell death through down-regulation of Fas ligand (FasL) (Del- gado M et al.
• a T-cell line (example?) was incubated together with the peptides and VIP or PACAP. After 10 days, the cells of the VIP/PACAP and HSA peptide treated as well as untreated control cell line cultures were collected by centrifugation and the chromosomal DNA was prepared using QIAamp DNA Mini Kit as recommended by the manufacturer (Quiagen, Hilden, Germany).
• the chromosomal DNAs were bisulphite treated as published, for example, according to Olek et al. 6 different multiplex PCR reactions were performed on the 3 bisulphite DNA samples (untreated control, HSA and VIP/PACAP treated samples) using Cy5 -labelled primer. The products of the methylation specific PCR reactions performed on the same DNA samples were combined. These complex mixtures of 64 PCR products derived from the three DNA samples were comparatively hybridised onto oligo micro anays representing 256 CpG and the methylation statuses of the CpGs were analysed according to a method described in WO 99/28498.
• macrophages were incubated with the CEA water extract which was added to culture media. After 10 days, the cells of the extract treated and the untreated control cell line cultures were collected by centrifugation and the chromosomal DNA was prepared using • QIAamp DNA Mini Kit as recommended by the manufacturer (Quiagen, Hilden, Germany).
• the chromosomal DNAs were bisulphite treated as published, for example, according to Olek et al. 6 different multiplex PCR reactions were performed on the 3 bisulphite DNA samples (untreated control and CEA treated samples) using Cy5 -labelled primer. The products of the methylation specific PCR reactions performed on the same DNA samples were combined. These complex mixtures of 64 PCR products derived from the three DNA samples were comparatively hybridised onto oligo micro anays representing 256 CpG and the methylation statuses of the CpGs were analysed (Olek et al. WO 99/28498). Comparison of three individual hybridisation assays of 2 complex PCRs independently performed on the 2 samples showed that the methylation status of CpGs of the IL-12, IL-2 and IFN-gamma genes were significantly changed by CEA water extract.
• ADM Adrenomedullin
• ANG Angiogenin, ribonuclease, RNase A family, 5
• ANGPT1 Angiopoietin 1
• ANGPT2 Angiopoietin 2
• ANGPT3 Angiopoietin 3
• ANGPT4 Angio- poietin 4
• ANPEP Al (membrane) aminopeptidase (aminopeptidase N, aminopeptidase M, microsomal aminopeptidase, CD13, pi 50)
• ARNT Aryl hydrocarbon receptor nuclear translocator
• BDK Braindykinin
• BDKRB2 Brainsomal aminopeptidase, CD13, pi 50
• BTN Butyrophilin
• CD 14 CD 14 antigen
• CD 19 CD 19 antigen
• CD ID CD ID antigen, d polypeptide
• CD2 CD2 antigen (p50), sheep red blood cell receptor
• CD20
• inducible factor 1, alpha subunit basic helix-loop-helix transcription factor
• IGF1 Insulinlike growth factor 1 (somatomedin C)
• IGF2 Insulin-like growth factor 2 (somatomedin A)
• ITGBL1 Integrin, beta-like 1 (with EGF-like repeat domains)
• JAG1 Jagged 1 (Alagille syndrome)
• JAG2 Jagged 2
• KAI1 Kangai 1 (suppression of tumorigenicity 6, prostate
• CD82 antigen R2 leukocyte antigen, antigen detected by monoclonal and antibody IA4
• KDR Kinase insert domain receptor (a type III receptor tyrosine kinase)
• LAG3 Lymphocyte-activation gene 3
• LAMA1 Laminin, alpha 1
• LAMA2 Longminin, alpha 2 (merosin, congenital muscular dystrophy)
• LAMA4 Laminin, alpha 4
• APAF1 Apoptotic protease activating factor
• API1 Apoptosis inhibitor 1
• API2 Apoptosis inhibitor 2
• API3 Apoptosis inhibitor 3
• API4 Apoptosis inhibitor 4 (survivin)
• BAD BCL2-antagonist of cell death
• BAD BCL2-antagonist of cell death
• BAG4 BCL2- associated athanogene 4
• BAK1 BCL2-antagonist/killer 1
• BAX BCL2-associated X protein
• BCL10 B-cell CLL/lymphoma 10
• BCL2 B-cell CLL/lymphoma 2
• BCL2A1 BCL2-related protein Al
• BCL2L1 BCL2-like 1
• BCL2L2 BCL2-like 2
• BNIP1 BCL2/adenovirus E1B 19kD-interacting protein 1
• BNIP2 BCL2/adeno virus E1B 19kD-interacting protein 2
• BNIP3 BCL2/adeno
• ADRA1A Adrenergic, alpha-lA-, receptor
• ADRA1C Adrenergic, alpha-lC-, receptor
• ADRA2A Adrenergic, alpha-2A-, receptor
• ADRA2B Adrenergic, alpha-2B-, receptor
• ADRA2C Adrenergic, alpha-2C-, receptor
• AD RBI Adrenergic, beta-1-, receptor
• ADRB2 Adrenergic, beta-2-, receptor, surface
• ADRB3 Adrenergic, beta-3-, receptor
• ADRBKl Adrenergic, beta, receptor kinase 1
• ADRBK2 Adrenergic, beta, receptor kinase 2
• COMT Catechol-O-methyltransferase
• DBH Dopamine beta-hydroxylase (dopamine beta-monooxygenase)
• DDC Dopa decarboxylase (aromatic L-amino acid decarbox
• ABL2 V-abl Abelson murine leukemia viral oncogene homolog 2 (arg, Abelson-related gene)); ACPI (Acid phosphatase 1, soluble); ACP2 (Acid phosphatase 2, lysosomal); ACP5 (Acid phosphatase 5, tartrate resistant); ACPP (Acid phosphatase, prostate); ACVR1B (Activin A receptor, type IB); ADK (Adenosine kinase); ADRBKl (Adrenergic, beta, receptor kinase 1); AK1 (Adenylate kinase 1); AK2 (Adenylate kinase 2); AK3 (Adenylate kinase 3); AKT1 (V-akt murine thymoma viral oncogene homolog 1); AKT2 (V-akt murine thymoma viral oncogene homolog 2); ALPI (Alkaline phosphatase, intestinal);
• CDC18L CDC 18 (cell division cycle 18, S.pombe, homolog)-like
• CDC2 Cell division cycle 2, Gl to S and G2 to M
• CDC25A Cell division cycle 25A
• CDC25A Cell division cycle 25A
• CDC25C Cell division cycle 25C
• CDC25C Cell division cycle 25C
• CDC27 Cell division cycle 27
• CDC2L1 Cell division cycle 2-like 1 (PITSLRE proteins)
• CDC42 Cell division cycle 42 (GTP-binding protein, 25kD)
• CDC7L1 CDC7 (cell division cycle 7, S.
• CDK2 Cyclin-dependent kinase 2
• CDK2 Cyclin-dependent kinase 2
• CDK5 Cyclin-dependent kinase 5
• CDK6 Cyclin-dependent kinase 6
• CDK6 Cyclin-dependent kinase 6
• CDK7 Cyclin-dependent kinase 7 (homolog of Xenopus MO 15 cdk-activating kinase)
• CDK7 Cyclin-dependent kinase 7 (homolog of Xenopus MO 15 cdk- activating kinase)
• CDK8 Cyclin-dependent kinase 8
• CDK8 Cyclin-dependent kinase 8
• CDKN1B Cyclin-dependent kinase inhibitor IB (p27, Kipl)
• CDKN1C Cyclin-dependent kinase inhibitor 1C
• IFI56 Interferon-induced protein 56
• IGFBP1 Insulin-like growth factor binding protein 1
• ILK Insulin-like growth factor binding protein 1
• INP10 Interferon (gamma)-induced cell line; protein 10 from); INPP5D (Inositol polyphosphate-5-phosphatase, 145kD); ISG20 (Interferon stimulated gene (20kD)); JAK1 (Janus kinase 1 (a protein tyrosine kinase)); JAK3 (Janus kinase 3 (a protein tyrosine kinase, leukocyte)); KDR (Kinase insert domain receptor (a type III receptor tyrosine kinase)); LCAT (Lecithin-cholesterol acyltransf erase); LIMK1 (LIM domain kinase 1); LIMK2 (LIM domain kinase 2); LRP1 (LIMK1 (LIM domain kinase 1
• MEKK3 MAP/ERK kinase kinase 3
• MEKK5 MAP/ERK kinase kinase 5
• MKI67 Antigen identified by monoclonal antibody Ki-67
• MST1R Macrophage stimulating 1 receptor (c-met- related tyrosine kinase)
• NCK1 NCK adaptor protein 1
• NEK3 NIMA (never in mitosis gene a)-related kinase)
• NME1 Non-metastatic cells 1, protein (NM23A) expressed in
• NME2 Non-metastatic cells 2, protein (NM23B) expressed in
• NOS2A Nitric oxide synthase 2A (inducible, hepatocytes)
• NPM1 Nucleophosmin (nucleolar phosphoprotein B23, nu- matrin)
• NTRK3 Neurotrophic tyrosine kinase, receptor, type 3
• RAD9 RAD9 (S. pombe) homolog
• RBL1 Retinoblastoma-like 1 (pi 07)
• RET Ret proto-oncogene (multiple endocrine neoplasia MEN2 A, MEN2B and medullary thyroid carcinoma 1 , Hirschsprang disease)
• RHOK Rhodopsin kinase
• ROCK1 Rho-associated, coiled-coil containing protein kinase 1
• RPS6KA2 Robosomal protein S6 kinase, 90kD, polypeptide 2
• RPS6KB1 Roso- mal protein S6 kinase, 70kD, polypeptide 1
• RYK RYK receptor-like tyrosine kinase
• SAPK3 Stress-activated protein kinase 3
• SERK1 SAPK Erk kinase 1
• SRC Stress-activated protein kinase 1
• ABL1 V-abl Abelson murine leukemia viral oncogene homolog 1
• ABL2 V-abl Abelson murine leukemia viral oncogene homolog 2 (arg, Abelson-related gene)
• ABR Active BCR- related gene
• ACPI Acid phosphatase 1, soluble
• ACP2 Acid phosphatase 2, lysosomal
• ACP5 Acid phosphatase 5, tartrate resistant
• ACPP Acid phosphatase, prostate
• ACTG1 Actin, gamma 1
• ACVR1B Activin A receptor, type IB
• ADD3 Additional aun 3 (gamma)
• ADK Adrenergic, beta, receptor kinase 1
• AIF1 Allograft inflammatory factor 1
• AK1 Adenylate kinase 1
• AK2 Adenylate kinase 2
• AK3 ABL1 (V-abl Abelson murine leukemia viral onc
• CDH13 (Cadherin 13, H-cadherin (heart)); CDH17 (Cadherin 17, LI cadherin (liver-intestine)); CDH2 (Cadherin 2, N-cadherin (neuronal)); CDH4 (Cadherin 4, R-cadherin (retinal)); CDH5 (Cadherin 5, VE-cadherin (vascular epithelium)); CDK2 (Cyclin-dependent kinase 2); CDK5 (Cyclin-dependent kinase 5); CDK6 (Cyclin-dependent kinase 6); CDK7 (Cyclin-dependent kinase 7 (homolog of Xenopus MO 15 cdk-activating kinase)); CDK8 (Cyclin-dependent kinase 8); CDKN2B (Cyclin- dependent kinase inhibitor 2B (pi 5, inhibit
• RASAl RAS p21 protein activator (GTPase activating protein) 1
• RET Ret proto-oncogene (multiple endocrine neoplasia MEN2A, MEN2B and medullary thyroid carcinoma 1, Hirschsprung disease)
• RGS1 (Regulator of G- protein signalling 1); RGS16 (Regulator of G-protein signalling 16); RGS7 (Regulator of G- protein signalling 7); RHOK (Rhodopsin kinase); ROCK1 (Rho-associated, coiled-coil containing protein kinase 1);
• RPS6KA2 Ribosomal protein S6 kinase, 90kD, polypeptide 2
• RPS6KB1 (Ribosomal protein S6 kinase, 70kD, polypeptide 1); RSN (Restin (Reed-Steinberg cell-expressed intermediate filament-associated protein)); RYK (RYK
• ACCPN Agenesis of corpus callosum and peripheral neuropathy (Andermann); ACVR1 (Activin A receptor, type I); ACVR1B (Activin A receptor, type IB); ACVR2 (Activin A receptor, type II); ACVR2B (Activin A receptor, type IIB); ACVRL1 (Activin A receptor type Il-like 1); ADFN (Albinism-deafness syndrome); AES (Amino-terminal enhancer of split); AFD1 (Acrofacial dysostosis 1, Nager type); AGC1 (Aggrecan 1 (chondroitin sulfate proteo- glycan 1, large aggregating proteoglycan, antigen identified by monoclonal antibody A0122)); AHO2 (Albright hereditary osteodystrophy-2); AIH3 (Amelogenesis imperfecta 3, hypomatu- ration or hypoplastic type); ALX3 (Aristaless-like homeobox 3); AMCD1 (Arthrogryposis multiplex congenital,
• DFFA DNA fragmentation factor, 45 kD, alpha subunit
• DNMT1 DNA (cytosine-5-)- methyltransferase 1
• DNMT2 DNA (cytosine-5-)-methyltransferase 2
• IGHMBP2 Immu- noglobulin mu binding protein 2
• LIG1 Liigase I, DNA, ATP-dependent
• LIG3 Ligase III, DNA, ATP-dependent
• LIG4 Ligase IV, DNA, ATP-dependent
• MGMT O-6- methylguanine-DNA methyltransferase
• NTHL1 Nth (E.coli endonuclease III)-like 1
• PRIM1 Primarymase, polypeptide 1 (49kD)
• RAG1 Recombination activating gene 1
• RFC3 Replication factor C (activator 1) 3 (38kD)
• RFC4 Replication factor C (activator 1) 4 (37kD)
• TERT Tel
• ADPRT ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)
• APEX APEX nuclease (multifunctional DNA repair enzyme)
• ATM Ataxia telangiectasia mutated (includes complementation groups A, C and D)
• BLM Bloom syndrome
• BRCA1 Breast cancer 1, early onset
• BRCA2 Breast cancer 2, early onset
• CKNl Cockayne syndrome 1 (classical)
• DDB1 Damage-specific DNA binding protein 1 (127kD)); DDB2 (Damage-specific DNA binding protein 2 (48kD)
• DDIT1 DNA-damage-inducible transcript 1
• DDIT1L DNA-damage-inducible transcript 1-like
• DDIT3 DNA-damage-inducible transcript 3
• DFFA DNA fragmentation factor, 45 kD, alpha subunit
• DNMT1 DNA (cytosine-5-)
• MSH2 MutS (E. coli) homolog 2 (colon cancer, nonpolyposis type 1)
• MSH3 MutS (E. coli) homolog 3
• MSH4 MutS (E. coli) homolog 4
• MSH5 MutS (E. coli) homolog 5
• MTH1 MutT (E.
• coli human homolog (8-oxo-7,8-dihydroguanosine triphosphatase)); NTHL1 (Nth (E.coli endonuclease III)-like 1); PMS1 (Postmeiotic segregation increased (S. cerevisiae) 1); PMS2 (Postmeiotic segregation increased (S.
• PMS2L1 Postmeiotic segregation increased 2-like 1
• PMS2L11 Postmeiotic segregation increased 2-like 1 1
• PMS2L12 Postmeiotic segregation increased 2-like 12
• PMS2L2 Postmeiotic segregation increased 2-like 2
• PMS2L3 Postmeiotic segregation increased 2-like 3
• PMS2L4 Postmeiotic segregation increased 2-like 4
• PMS2L5 Postmeiotic segregation increased 2-like 5
• PMS2L6 Postmeiotic segregation increased 2-like 6
• PMS2L8 Postmeiotic segregation increased 2-like 8
• PMS2L9 Postmeiotic segregation increased 2-like 9
• POLB Polymerase (DNA directed), beta
• PRIM1 Primarymase, polypeptide 1 (49kD)
• PRKDC Protein kinase, DNA-activated, catalytic polypeptide
• RAD1 RAD1 (S.
• RAD17 (RAD17 (S. pombe) homolog); RAD21 (RAD21 (S. pombe) homolog); RAD23A (RAD23 (S. cerevisiae) homo- log A); RAD23B (RAD23 (S. cerevisiae) homolog B); RAD51 (RAD51 (S. cerevisiae) ho- molog (E coli RecA homolog)); RAD51C (RAD51 (S. cerevisiae) homolog C); RAD51L1 (RAD51 (S. cerevisiae)-like 1); RAD51L3 (RAD51 (S. cerevisiae)-like 3); RAD52 (RAD52 (S.
• ADAR AdAR (Adenosine deaminase, RNA-specific); ADPRT (ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)); ATM (Ataxia telangiectasia mutated (includes complementation groups A, C and D)); ATR (Ataxia telangiectasia and Rad3 related); ATRX (Alpha thalassemia/mental retardation syndrome X-linked); BLM (Bloom syndrome); CENPB (Centromere protein B (80kD)); CENPC1 (Centromere protein C 1); CHD4 (Chromodomain heli- case DNA binding protein 4); CHDL (Chromodomain-helicase-DNA-binding protein); CKN1 (Cockayne syndrome 1 (classical)); DNA2L (DNA2 (DNA replication helicase, yeast, ho- molog)-like); DNASE1 (Deoxyribonuclease I); DNASE
• pombe checkpoint homolog
• LIG2 Limitogen-dependent
• MLH1 MotL (E. coli) homolog 1 (colon cancer, nonpolyposis type 2)
• MSH5 MutS (E. coli) homolog 5
• POLA Polymerase (DNA directed), alpha
• POLB Polymerase (DNA directed), beta
• POLD1 Polymerase (DNA directed), delta 1, catalytic subunit (125kD)
• RAD1 RAD1 (S. pombe) homolog
• RAD50 RAD50 (S. cerevisiae) homolog
• RAD51 RAD51 (S.
• ADA Addenosine deaminase
• ADPRT ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)
• ADSS AdSS (Adenylosuccinate synthase); AHR (Aryl hydrocarbon receptor); ATBF1 (AT-binding transcription factor 1); ATF3 (Activating transcription factor 3); BARD1 (BRCA1 associated RING domain 1); CBF2 (CCAAT-box-binding transcription factor); CBFA2 (Core-binding factor, runt domain, alpha subunit 2 (acute myeloid leukemia 1 ; amll oncogene)); CBFA3 (Core-binding factor, runt domain, alpha subunit 3); CBFB (Core-binding factor, beta subunit); CEBPA (CCAAT/enhancer binding protein (C/EBP), alpha); CEBPB (CCAAT/enhancer binding protein (C/EBP), beta); CEBPD (CCA
• A1BG Alpha-1-B glycoprotein
• A2M Alpha-2-macro globulin
• AAA Achalasia- addisonianism-alacrimia syndrome (Allgrove syndrome);
• AABT Beta-amino acids, renal transport of);
• AACT Alpha- 1-antichymotrypsin
• AARS Alanyl-tRNA synthetase
• ABAT 4-aminobutyrate aminotransferase
• ABC7 ATP-binding cassette 7
• ABO ABO blood group (transferase A, alpha); 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3- galactosyltransferase);ACADL (Acyl-Coenzyme A dehydrogenase, long chain); ACADM (Acyl-Coenzyme A dehydrogenase, C-4 to C-12 straight chain); AC ADS (Acyl-Coenzy
• HSD1L2 HMT1 (hnRNP methyltransferase, S. cerevisiae)-like 2
• HRY Hairy (Drosophila)-homolog
• HSD17B3 Hydroxysteroid (17-beta) dehydrogenase 3
• HSD3B1 Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1
• HSD3B2 Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2
• HSPA1A Heat shock 70kD protein 1
• HSPA1L Heat shock 70kD protein-like 1
• HSPA2 Heat shock 70kD protein 2
• HSPA6 Heat shock 70kD protein 6 (HSP70B')
• HSPG2 Heparan sulfate proteoglycan 2 (perlecan)
• HSPA1A Heat shock 70kD
• MACAM1 Mocosal addressin cell adhesion molecule- 1
• MADH1 MAD (mothers against decapentaplegic, Drosophila) homolog 1
• MADH2 MAD (mothers against decapentaplegic, Drosophila) homolog 2
• MADH4 MAD (mothers against decapentaplegic, Drosophila) homolog 4
• MAGEA1 Melanoma antigen, family A, 1 (directs expression of antigen MZ2-E)
• MAGEB1 Melanoma antigen, family B, 1
• MAL Main, T-cell differentiation protein
• MALL Main, T-cell differentiation protein-like
• MANB Mannosidase, alpha B, lysosomal
• MAP IB Microtubule-associated protein IB
• MAPKAPK3 Mitogen-activated protein kina- se-activated protein kinase 3
• MASP1 Mannan-binding
• MMP12 Matrix metalloproteinase 12 (macrophage elastase)
• MMP13 Matrix metalloproteinase 13 (collagenase 3)
• MMP14 Matrix metalloproteinase 14 (membrane-inserted)
• MMP15 Matrix metalloproteinase 15 (membrane- inserted)
• MMP16 Matrix metalloproteinase 16 (membrane-inserted)
• MMP17 Matrix metalloproteinase 17 (membrane-inserted)
• MMP18 Matrix metalloproteinase 18
• MMP19 Matrix metalloproteinase 19
• PNMT Phenylethanolamine N-methyltransferase
• PNUTL1 Peanut (Drosophila)- like 1
• POLB Polymerase (DNA directed), beta)
• POMC Proopiomelanocortin (adrenocor- ticotropin/beta-lipotropin alpha-melanocyte stimulating hormone/beta-melanocyte stimulating hormone/ beta-endorphin)
• PON1 (Paraoxonase 1); PON2 (Paraoxonase 2); PORC (Por- phyria, acute; Chester type); POU2AF1 (POU domain, class 2, associating factor 1); POU5F1 (POU domain, class 5, transcription factor 1);
• PPBP Pro-platelet basic protein (includes platelet basic protein, beta-thromboglobulin, connective tissue-activating peptide III, neutrophil- activating peptide-2)
• PPCD Posterior polymorphous corneal
• pombe homolog
• RAD51L3 RAD51 (S. cerevisiae)-like 3
• RAF1 V-raf-1 murine leukemia viral oncogene homolog 1
• RAG1 Recombination activating gene 1
• RAG2 Recombination activating gene 2
• RANBP3 RAN binding protein 3
• RAP1A RAP1A, member of RAS oncogene family
• RBI Retinoblastoma 1 (including osteosarcoma)
• RBP4 Retinol-binding protein 4, interstitial
• RBS Robotts syndrome
• RCN2 Reticulocalbin 2, EF-hand calcium binding domain
• RCP Red cone pigment (color blindness, protan)
• RCV1 Recoverin
• RDBP RD RNA-binding protein
• RDS Retinal degeneration, slow (retinitis pigmentosa 7)
• RELA V-rel avian reticuloendotheliosis
• SLC12A1 Solute carrier family 12 (sodium/potassium/chloride transporters), member 1); SLC14A1 (Solute canier family 14 (urea transporter), member 1 (Kidd blood group)); SLC18A2 (Solute carrier family 18 (vesicular monoamine), member 2); SLC1A5 (Solute canier family 1 (neutral amino acid transporter), member 5); SLC20A1 (Solute canier family 20 (phosphate transporter), member 1); SLC20A2 (Solute canier family 20 (phosphate transporter), member 2); SLC2A1 (Solute canier family 2 (facilitated glucose transporter), member 1); SLC2A2 (Solute canier family 2 (facilitated glucose transporter), member 2); SLC2A4 (Solute carrier family 2 (facilitated glucose transporter), member 4); SLC3A1 (Solute canier family 3 (cystine, dibasic and neutral amino acid transporters, activator of cystine, dibasic
• pombe homolog
• WFS Wilfram syndrome
• WT1 Wildms tumor 1
• WT3 Wildms tumor- 3
• WWS Wild-Wolff syndrome
• XBPl X-box binding protein 1
• XG Xg blood group (pseudoautosomal boundary-divided on the X chromosome)
• XGR Expression of XG and MIC2 on erythrocytes
• XK Kerthrocytes
• XK Kerthrocytes
• XK Kerthrocytes
• XK Kerthrocytes
• XK Kerocyte blood group precursor (McLeod phenotype)
• XPA Xeroderma pigmentosum, complementation group A
• XPC Xeroderma pigmentosum, complementation group C
• XPNPEPL X-prolyl aminopeptidase (aminopeptidase P)-like
• XRCC1 X-ray repair
• ACAT1 (Acetyl-Coenzyme A acetyltransferase 1 (acetoacetyl Coenzyme A thiolase); ACAT2 (Acetyl-Coenzyme A acetyltransferase 2 (acetoacetyl Coenzyme A thiolase); ACATN (Acetyl-Coenzyme A transporter; BCAT1 (Branched chain aminotransferase 1, cytosolic; CRAT (Carnitine acetyltransferase; DIA4 (Diaphorase (NADH/NADPH) (cytochrome b-5 reductase); DUSP2 (Dual specificity phosphatase 2; EPHX1 (Epoxide hydrolase 1, microsomal (xenobiotic); EPHX2 (Epoxide hydrolase 2, cytoplasmic; GATM (Glycine amidinotransferase (L-arginine: glycine amidinotransferase
• ACTG1 Actin, gamma 1
• ADD3 Additional adjucocyte cell adhesion molecule
• ALCAM Activated leucocyte cell adhesion molecule
• ANK1 Ankyrin 1, erythrocytic
• ANPEP Al (membrane) aminopeptidase (aminopeptidase N, aminopeptidase M, microsomal aminopeptidase, CD13, pi 50)); BTN (Butyrophilin); CD14 (CD14 antigen); CD19 (CD19 antigen); CD1D (CD1D antigen, d polypeptide); CD2 (CD2 antigen (p50), sheep red blood cell receptor); CD20 (CD20 antigen); CD22 (CD22 antigen); CD33 (CD33 antigen (gp67)); CD34 (CD34 antigen); CD37 (CD37 antigen); CD38 (CD38 antigen (p45)); CD39 (CD39 antigen); CD4 (CD4 antigen (p55)); CD44 (CD44 antigen
• AREG Adiregulin (schwannoma-derived growth factor)
• BCGF1 B-cell growth factor 1 (12kD)
• CTGF Connective tissue growth factor
• CTGF-L Connective tissue growth factorlike protein
• ECGF1 Endothelial cell growth factor 1 (platelet-derived)
• EGF Epidermal growth factor
• EPS 15 Epidermal growth factor receptor pathway substrate 15
• EPS8 Epidermal growth factor receptor pathway substrate 8
• FGF1 Fibroblast growth factor 1 (acidic)
• FGF10 (Fibroblast growth factor 10); FGF11 (Fibroblast growth factor 11); FGF12B (Fibroblast growth factor 12B); FGF13 (Fibroblast growth factor 13); FGF14 (Fibroblast growth factor 14); FGF16 (Fibroblast growth factor 16);
• FGF6 Fibroblast growth factor 6
• FGF7 Fibroblast growth factor 7 (keratinocyte growth factor)
• FGF8 Fibroblast growth factor 8 (androgen-induced)
• FGF9 F
• C5 Complement component 5
• CAD Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase
• CATR1 CATR tumorigenicity conversion 1
• CDR1 Cerebellar degeneration-related protein (34kD)
• CHGB Chromogranin B (secretogranin 1)
• CHIT1 Chitinase 1
• COL9A2 Coldlagen, type IX, alpha 2
• COX10 Cytochrome c oxidase subunit X (heme A: farnesyltransferase)
• COX11 Cytochrome c oxidase subunit 11
• COX15 Cytochrome c oxidase subunit 15
• COX17 Human homolog of yeast mitochondrial copper recruitment gene
• COX5A Cytochrome c oxidase subunit Va
• COX5B Cytochrome c oxidase
• GZMK cytotoxic T-lymphocyte-associated serine esterase 1
• GZMK GZMK
• HGFAC HGF activator
• HRMT1L2 HMT1 (hnRNP methyltransferase, S.
• HSJ1 Heat shock protein, neuronal DNAJ-like 1
• HSJ2 Heat shock protein, DNAJ-like 2
• IDUA Iduronidase, alpha-L-
• IGFBP10 Insulinlike growth factor binding protein 10
• LDHA Lactate dehydrogenase A
• LDHB Lactate dehydrogenase B
• LGALS1 Lectin, galactoside-binding, soluble, 1 (galectin 1)
• LMO1 LIM domain only 1 (rhombotin 1)
• LNPEP Leucyl/cystinyl aminopeptidase
• LPP LIM domain-containing prefened translocation partner in lipoma
• MANA2 Mannosidase, alpha type II
• MAOA Monoamine oxidase A
• MFNG Manic fringe (Drosophila) homolog
• MMP-20 Enamelysin
• MMP10 Matrix
• ALDH1 Aldehyde dehydrogenase 1, soluble
• ALDH10 Aldehyde dehydrogenase 10 (fatty aldehyde dehydrogenase)
• ALDH2 Aldehyde dehydrogenase 2, mitochondrial
• ALDH3 Aldehyde dehydrogenase 3
• ALDH6 Aldehyde dehydrogenase 6
• ALDH7 Aldehyde dehydrogenase 7
• ALDH8 Aldehyde dehydrogenase 8
• ANT2 Adenine nucleotide translo- cator 2 (fibroblast)
• APEX APEX nuclease (multifunctional DNA repair enzyme)
• BCHE Butyrylcholinesterase
• BLMH Bleomycin hydrolase
• CAT Catalase
• CDA Cytidine deaminase
• CYP11A Cytochrome P450, subfamily XIA
• ABLl V-abl Abelson murine leukemia viral oncogene homolog 1
• ABL2 V-abl Abelson murine leukemia viral oncogene homolog 2 (arg, Abelson-related gene)
• ABR Active BCR- related gene
• ACVR1B ACVR1B (Activin A receptor, type IB)
• ADK Adrenosine kinase
• ADRBKl Adrenergic, beta, receptor kinase 1
• AK1 Adrenergic, beta, receptor kinase 1
• AK1 Adrenergic, beta, receptor kinase 1
• AK1 Adrenergic, beta, receptor kinase 1
• AK1 Adrenergic, beta, receptor kinase 1
• AK1 Adrenergic, beta, receptor kinase 1
• AK1 Adrenergic, beta, receptor kinase 1
• AK2 Adrenergic, beta, receptor kinase 1
• CDK2 Cyclin-dependent kinase 2
• CDK5 Cyclin- dependent kinase 5
• CDK6 Cyclin-dependent kinase 6
• CDK7 Cyclin-dependent kinase 7 (homolog of Xenopus MO 15 cdk-activating kinase)
• CDK8 Cyclin-dependent kinase 8
• CDKN2B Cyclin-dependent kinase inhibitor 2B (pi 5, inhibits CDK4)
• CHEK1 CHK1 (checkpoint, S.pombe) homolog
• CHN1 Chimerin (chimaerin) 1
• CHN2 Chimerin (chima- erin) 2
• CHUK Consserved helix-loop-helix ubiquitous kinase
• CIS4 STAT induced STAT inhibitor-4
• CKS1 CDC28 protein kinase 1
• CKS2 CDC28 protein kinase 1
• CKS2 CDC28 protein
• MADH3 MAD (mothers against decapentaplegic, Drosophila) homolog 3
• MAPKAPK2 Mitogen-activated protein kinase- activated protein kinase 2
• MAPKAPK5 Mitogen-activated protein kinase-activated protein kinase 5
• MATK Megakaryocyte-associated tyrosine kinase
• MEKK3 MAP/ERK kinase kinase 3
• MEKK4 MAP/ERK kinase kinase 4
• MEKK5 MAP/ERK kinase kinase 5
• MSTIR Macrophage stimulating 1 receptor (c-met-related tyrosine kinase)
• NCKl NCK adaptor protein 1
• NEK3 NIMA (never in mitosis gene a)-related kinase
• NMEl Non- metastatic cells 1, protein (NM23A) expressed in);
• PIASX-BETA Protein inhibitor of activated STAT X
• PIK3C3 Phosphoinositi- de-3-kinase, class 3
• PIK3CA Phosphoinositide-3 -kinase, catalytic, alpha polypeptide
• PIK3CA Phosphoinositide-3 -kinase, catalytic, alpha polypeptide
• PIK3CG Phosphoinositi- de-3-kinase, catalytic, gamma polypeptide
• PIM1 Pim-1 oncogene
• PLA2G2A Phospholi- pase A2, group IIA (platelets, synovial fluid)
• PLCB4 Phospholipase C, beta 4
• PLCE Phospholipase C, epsilon
• PLCG2 Phospholipase C, gamma 2 (phosphatidylinosito
• ADA Addenosine deaminase
• ADPRT ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)
• ADSS AdSS (Adenylosuccinate synthase); AHR (Aryl hydrocarbon receptor); ATBF1 (AT-binding transcription factor 1); ATF1 (Activating transcription factor 1); ATF3 (Activating transcription factor 3); ATF4 (Activating transcription factor 4 (tax-responsive enhancer element B67)); BARD1 (BRCAl associated RING domain 1); BCL6 (B-cell CLL/lymphoma 6 (zinc finger protein 51)); BMZF2 (Zinc finger 2, bone marrow); BMZF3 (Bone manow zinc finger 3); CBF2 (CCAAT-box-binding transcription factor); CBFA2 (Core-binding factor, runt domain, alpha subunit 2 (acute myeloid leukemia 1; amll oncogene)); CBFA3
• MDM2 Manton muscleblind B protein
• MDM2 Mantone double minute 2, human homolog of; p53-binding protein
• MHC2TA MHC class II transactivator
• MKI67 Antigen identified by monoclonal antibody Ki-67
• MNDA Myeloid cell nuclear differentiation antigen
• MSX1 Msh (Drosophila) homeo box homolog 1 (formerly homeo box 7)
• MTHFD 5,10- methylenetetrahydrofolate dehydrogenase, 5,10-methylenetetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthetase
• MYC V-myc avian myelocytomatosis viral oncogene homolog
• NCBP Nuclear cap binding protein, 80kD
• NCBP Nuclear cap binding protein, 80kD
• NDP52 Nuclear domain 10 protein
• NFE2 Nuclear factor (erythroid-derived 2), 45kD
• ABLl V-abl Abelson murine leukemia viral oncogene homolog 1
• ABL2 V-abl Abelson murine leukemia viral oncogene homolog 2 (arg, Abelson-related gene)
• AKT1 V-akt murine thymoma viral oncogene homolog 1
• AKT2 V-akt murine thymoma viral oncogene homolog 2
• APC Adomatosis polyposis coli
• ARAF1 V-raf murine sarcoma 3611 viral oncogene homolog 1
• ARAF2 V-raf murine sarcoma 3611 viral oncogene homolog 2
• ARHA Ras homolog gene family, member A
• ARHB Ras homolog gene family, member B
• ARHC Ras homolog gene family, member C
• AXL AXL receptor tyrosine kinase
• BCL2 B-cell CLL/lymphoma 2
• BCL2 B-
• coli colon cancer, nonpolyposis type 2
• MOS V-mos Moloney murine sarcoma viral oncogene homolog
• MPL Myeloproliferative leukemia vims oncogene
• MSH2 MutS (E.
• MYB V-myb avian myeloblastosis viral oncogene homolog
• MYBL1 V-myb avian myeloblastosis viral oncogene homolog-like 1
• MYBL2 V-myb avian myeloblastosis viral oncogene homolog-like 2
• MYC V-myc avian myelocytomatosis viral oncogene homolog
• MYCL1 V-myc avian myelocytomatosis viral oncogene homolog 1, lung carcinoma derived
• MYCL2 V-myc avian myelocytomatosis viral oncogene homolog 2
• MYCLK1 V-myc avian myelocytomatosis viral oncogene homolog-like 1
• MYCN V-myc avian
• TALI T-cell acute lymphocytic leukemia 1
• TGFBR2 Transforming growth factor, beta receptor II (70-80kD)
• ⁇ PO Thrombopoietin (myeloproliferative leukemia virus oncogene ligand, megakaryocyte growth and development factor)
• THRA thyroid hormone receptor, alpha (avian erythroblastic leukemia viral (v-erb-a) oncogene homolog)
• THRB thyroid hormone receptor, beta (avian erythroblastic leukemia viral (v-erb-a) oncogene homolog 2)
• TIAM1 T-cell lymphoma invasion and metastasis 1
• TIM Oncogene TIM
• TM4SF1 Transmembrasis 1
• coli homolog 1 (colon cancer, nonpolyposis type 2)); MSH2 (MutS (E. coli) homolog 2 (colon cancer, nonpolyposis type 1)); NBLl (Neuroblastoma candidate region, suppression of tumorigenicity 1); NF1 (Neurofibromin 1 (neurofibromatosis, von Reck- linghausen disease, Watson disease)); NF2 (Neurofibromin 2 (bilateral acoustic neuroma)); NFKB2 (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/pl00)); NKTR (Natural killer-tumor recognition sequence); NMEl (Non-metastatic cells 1, protein (NM23A) expressed in); NOV (Nephroblastoma overexpressed gene); NTRKl (Neurotrophic tyrosine kinase, receptor, type 1); PDGFRL (Platelet-derived growth factor receptor-like
• TALI T-cell acute lym- phocytic leukemia 1
• TGFBR2 Transforming growth factor, beta receptor II (70-80kD)
• TIAM1 T-cell lymphoma invasion and metastasis 1
• TIM Oncogene TIM
• TM4SF1 Transmembrane 4 superfamily member 1
• TNF Tumor necrosis factor (TNF superfamily, member 2)
• TP53 Tuor protein p53 (Li-Fraumeni syndrome)
• TP53BP2 Tuor protein p53-binding protein, 2
• TP73 Tuor protein p73
• VHL Volon Hippel-Lindau syndrome
• WNT1 Wi-type MMTV integration site family, member 1
• WNT1 Wi-type MMTV integration site family, member 1
• WNT1 Wi-type MMTV integration site family, member 1
• WNT1 Wi-type MMTV integration site family, member 1
• WNT1 Wi-type MMTV integration site family, member

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• 2002
  • 2002-03-01 CA CA002439779A patent/CA2439779A1/en not_active Abandoned
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